KR20090088564A - Pharmaceutical preparation containing choline alfoscerate - Google Patents

Abstract

A pharmaceutical preparation containing a choline alfoscerate is provided to easily produce the preparation using colloidal silicon dioxide and water-soluble polymer. A pharmaceutical preparation containing a choline alfoscerate comprises the choline alfoscerate in which colloidal silicon dioxide is absorbed. The choline alfoscerate absorbs to 0.5-1.5wt.pt. of colloidal silicon dioxide. A method for producing the pharmaceutical preparation containing choline alfoscerate comprises: a step of absorbing the choline alfoscerate to colloidal silicon dioxide; and a step of producing a granule using a colloidal silicon dioxide with hydroxypropylmethylcellulose, polyvinylpyrrolidone or their mixture.

Description

Pharmaceutical preparation containing choline alfoscerate

The present invention relates to choline alfoscerate-containing preparations with improved storage stability and ease of taking, and methods for their preparation.

Choline alfoscerate is a drug used to treat secondary symptoms caused by cerebrovascular injury and degenerative or degenerative cerebral psychiatric syndromes, including cognitive impairment such as memory loss, confusion, disorientation, and decreased concentration; Emotional and behavioral changes such as emotional anxiety, irritability, etc .; It is known to be useful for senile pseudodepression.

Existing choline alfoscerate formulation is a formulation containing liquid choline alfoscerate in soft capsules, and the active ingredient may transition to water-soluble soft gelatin coatings over time. It is necessary to use preservatives in order to reduce the possibility of microbial alteration of soft capsule preparations, gelatin capsules are weak to moisture and heat, which may cause disintegration delay during storage, especially in elderly patients with poor swallowing ability. The disadvantage is that it is inconvenient.

Therefore, the problem to be solved by the present invention is to provide a choline alfoscerate-containing pharmaceutical formulation with excellent storage stability and improved ease of taking.

Another problem to be solved by the present invention is to provide a method for preparing a choline alfoscerate-containing pharmaceutical formulation with improved storage stability and ease of taking.

In order to achieve the above object, the present invention provides a choline alfoscerate-containing pharmaceutical preparation comprising choline alfoscerate adsorbed on colloidal silicon dioxide, preferably the choline alfoscerate Provides a pharmaceutical formulation, characterized in that adsorbed on 0.5 to 1.5 parts by weight of colloidal silicon dioxide relative to the weight of choline alfoscerate.

Colloidal silicon dioxide is most preferred among various excipients as a component for adsorbing liquid choline alfoscerate. Lactose has a high specific gravity when preparing powders / granules, a relatively small surface area and low adsorptivity, making it difficult to control the properties of the main component of choline alfoscerate. Since it is wet, there is a high possibility of sticking phenomenon during tableting or capsule filling, and therefore, a large amount of coating polymer must be used. Hydroxypropylmethylcellulose (hydroxypropylmethylcellulose) is suitable for adsorption of main components due to low specific gravity and somewhat hygroscopicity and swelling when preparing powders / granules, but has disadvantages such as uneven particle size and difficulty in sieving process. When the solid preparation is prepared, the properties of the inclusions are relatively good, but the particles become very hard after drying and due to their viscosity during tableting or capsule filling, there is a problem in that disintegration is delayed. Hydroxypropyl cellulose has a high viscosity when preparing powders / granules, so that the particles are very firmly caught after drying, the particle size is uneven, and the sieving is difficult, and when preparing solid preparations such as tablets, powders / granules can be prepared. In addition to the problem of time, there is a disadvantage that the disintegration is delayed. In the case of polyvinylpyrrolidone, the adsorbed clathrate has good properties, and the granular particles are also relatively uniform compared to the viscosity, and there is no problem in sieving. In case of high viscosity, disintegration is delayed.

In addition, when the colloidal silicon dioxide is used, the amount thereof is preferably 0.5 to 1.5 parts by weight based on the weight of the main component of choline alfoscerate. If the amount of colloidal silicon dioxide used is less than 0.5 parts by weight, it is difficult to control the physical properties of the main liquid component, and there is a risk of sticking phenomenon during tableting and capsule filling. There is a problem that arises, there is a possibility that disintegration is delayed when preparing a solid preparation such as tablets.

In addition, the pharmaceutical preparations according to the present invention are water-soluble polymers, preferably hydroxypropylmethylcellulose and polyvinylpyrrolidone, more preferably hydroxypropyl, than simply containing silicon dioxide adsorbed with choline alfoscerate. After preparing choline alfoscerate-adsorbed silicon dioxide using methyl cellulose in granular form, it is preferable to contain such granules (or fine granules) in terms of property stability, ease of manufacturing process such as filling, and the like. Further contemplated, it is further preferred that such pharmaceutical preparations are powders or granules. In addition, the hydroxypropyl methyl cellulose is more preferably a viscosity of 3 to 7 cP as measured by a 2% aqueous solution at 20 ℃.

Hydroxypropylcellulose, poloxamer, polyox, carrageenan and the like may be used as polymers for preparing granules, but these polymers are less preferred than the hydroxypropylmethylcellulose and polyvinylpyrrolidone, and have stability. Hydroxypropylmethylcellulose is more preferred than polyvinylpyrrolidone.

In the case of polyvinylpyrrolidone, the adsorbed clathrate has good properties, and the viscosity of the granule liquid is low, so that granules can be produced even with a small amount of granule solvent. There is a possibility that, when dried and solidified, the viscosity is relatively high, so that disintegration may be delayed in the case of a formulation such as a tablet. In the case of hydroxypropyl cellulose has a problem that the process time is long, because the amount of the granular solvent must be increased due to the high viscosity, the particles are very hard after drying, for this reason there is a problem that the hardness is high and the disintegration is delayed when manufacturing tablets . In the case of poloxamer, the granules and granules have good properties, but the coating efficiency is low. Therefore, a large amount of poloxamer should be used in comparison with other polymers to prevent the migration and soaking of the main component. In the case of polyox, the storage stability is poor due to heat and moisture resistance. When preparing granules using carrageenan, there is a problem in that the particle size is uneven and disintegration is very delayed.

The pharmaceutical preparations according to the present invention are additional components such as fillers, disintegrants, excipients, flavoring agents, sweeteners, glidants, etc., in addition to water-soluble polymers for preparing granules and colloidal silicon dioxide, which is an adsorbent for adsorbing liquid choline alfoscerate. It may include.

The pharmaceutical preparations according to the invention are preferably in the form of powders or granules, but tablets prepared by tableting such powders or granules, capsules prepared by filling such powders or granules, are also included in the scope of the invention.

The present invention also comprises adsorbing (S1) choline alfoscerate to 0.5 to 1.5 parts by weight of colloidal silicon dioxide relative to the weight of choline alfoscerate; And (S2) preparing choline alfoscerate-containing pharmaceutical preparations, comprising preparing colloidal silicon dioxide adsorbed choline alfoscerate into granules using hydroxypropylmethylcellulose.

As such, the present invention provides excellent choline alfoscerate-containing pharmaceutical formulations and a method for preparing such pharmaceutical formulations, which are excellent in storage stability, do not require a separate soft capsule manufacturing facility in preparation.

Hereinafter, the present invention will be described in detail with reference to Examples. However, embodiments according to the present invention can be modified in many different forms, the scope of the present invention should not be construed as limited to the embodiments described below. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Example 1 Selection of Excipients for Adsorption

To prepare a pharmaceutical formulation containing choline alfoscerate with the components and contents as shown in Table 1, and evaluated the various effects according to the type of excipient for adsorption.

No. Ingredient (mg) Example 1-1 1-2 1-3 1-4 1-5 a choline alfoscerate 200 200 200 200 200 b colloidal silicon dioxide 200 100 100 100 100 lactose - 100 - - - hydroxypropylmethylcellulose - - 100 - - hydroxypropylcellulose - - - 100 - polyvinylpyrrolidone - - - - 100 c hydroxypropylmethylcellulose 120 120 120 120 120 d microcrystalline cellulose 93.5 93.5 93.5 93.5 93.5 e crospovidone 18 18 18 18 18 f polyethyleneglycol6000 12 12 12 12 12 g magnesium stearate 6.5 6.5 6.5 6.5 6.5 h water Quantity Quantity Quantity Quantity Quantity i ethanol Quantity Quantity Quantity Quantity Quantity

More specifically, choline alfoscerate-containing tablets were prepared and evaluated by the following two methods.

First, the components a, b and i were mixed and sieved to make a seed. Thereafter, the components c, f and h were mixed to dissolve or disperse to form a coating solution, and then the seeds were flowed on the fluidized bed of the fluidized bed granulator, followed by spraying the coating solution and drying to prepare fluidized bed granules. The granules were dried on a fluid bed granulator and after being granulated, the components d, e and g were postmixed and compressed.

Alternatively, choline alfoscerate-containing tablets were prepared using the following method. Components a, b, and i were sieved after mixing. Components c, f and h were mixed and dissolved or dispersed to form a binding solution, and the binding solution and choline alfoscerate mixture were mixed on a mixer. The resulting mixture was granulated and stipulated, dried and the components d, e and g were mixed. Thereafter, the obtained mixture was compressed.

As a result of observing the manufacturing process, in Example 1-1, the clathrate property was good, and both mixing and tableting processes were easy. In the case of Example 1-2, the mixing and tableting process was good, but the inclusions were slightly wet and the size of the particles before tableting was uneven. In the case of Example 1-3, the physical properties of the main component was removed at the time of inclusion, but a lot of lumps were formed in the granules, and the particle size was uneven even after the formulation. In Example 1-4, the physical properties of the main component were not completely removed during inclusion, and the viscosity of the coating liquid or the bonding liquid was large, resulting in uneven and hard particles. In the case of Example 1-5, the physical properties of choline alfoscerate as a main component in inclusion were not completely removed. These results indicate that colloidal silicon dioxide is useful as an excipient for adsorbing choline alfoscerate.

Disintegration time was measured using the tablets prepared in Examples 1-1 to 1-5 according to the disintegration test method which was collected in the Korean Pharmacopoeia. The results are shown in Table 2 below.

Example Disintegration time (minutes) 1-1 9 1-2 13 1-3 15 1-4 23 1-5 21

As shown in Table 2, the disintegration time of Example 1-1 was the best within 10 minutes. In the above embodiments, the tablet weight is very large, with a tablet weight of 650 mg. Therefore, when trying to reduce the weight of tablets, it is inevitable to delay the disintegration time because it will inevitably reduce the amount of disintegrants and excipients. It can be seen that silicon dioxide is useful.

Example 2 Evaluation of Adsorption Excipients and Main Component Ratios

To prepare a granule containing choline alfoscerate with the ingredients and contents as shown in Table 3, and evaluated the various effects according to the ratio of the excipient for adsorption and the main component of choline alfoscerate.

No Ingredient (mg) Example 2-1 2-2 2-3 2-4 2-5 a Choline alfoscerate 400 400 400 400 400 b colloidal silicon dioxide 800 600 500 300 200 c hydroxypropylmethylcellulose 40 95 150 250 350 d lactose 50 - - - - e mannitol 80 75 85 125 115 f aspartame 15 15 15 15 15 g polyethyleneglycol6000 5 10 15 25 35 h sugar 775 770 800 850 850 i citric acid 20 20 20 20 20 j flavor 15 15 15 15 15 k water Quantity Quantity Quantity Quantity Quantity l ethanol Quantity Quantity Quantity Quantity Quantity Sum 2,200 2,000 2,000 2,000 2,000

It was prepared using a fluidized bed granulator as described below, or a choline alfoscerate-containing granule was prepared using a general granulator.

When using a fluid bed granulator was prepared as follows. Components a, b and l were mixed and sieved to use as seeds. Thereafter, components c, (d,) g and k were mixed and dissolved or dispersed to prepare a coating solution. Fluidized granules were sprayed onto the seed flowing in the fluidized bed to form fluidized bed granules, and the granules were dried and granulated before finally mixing the components e, f, h, i and j.

It was prepared as follows using a general mixing method. Components a, b and l were sieved after mixing. Components c, (d,) g and k were mixed to dissolve or dispersed to form a binding liquid, and the binding liquid and the mixture were mixed on a mixer. The granules thus prepared were granulated, sintered, dried, and finally mixed with components e, f, h, i and j to prepare choline alfoscerate-containing granules.

The manufacturing process and the resulting granules were visually evaluated. In Examples 2-1 and 2-2, the amount of colloidal silicon dioxide was 150% or more relative to the main component in the liquid phase, so that the properties of the clathrate were good, but the adhesion between the clathrate particles decreased so that the ratio of colloidal silicon dioxide Increasing the amount of fines generated during the process increased, thereby maximizing the surface area of the particles, resulting in lower coating efficiency when the same amount of polymer (hydroxypropylmethylcellulose in Example 2) was used in the subsequent granulation. Large amounts of polymer are required and show lower production yields. As a result, liquid choline alfoscerate was more likely to bleed out, and the particle size was significantly reduced compared to the powder formulation standard. In Example 2-5, in which the amount of colloidal silicon dioxide as an adsorbent was 50% of the main component, the incidence of fine powder was decreased, but it was difficult to sufficiently offset the properties of the liquid main component. Example 2-4 was most suitable in consideration of the manufacturing process, the properties of the inclusions, the amount of fines generated during the manufacturing process, and stability.

Example 3 Evaluation of Polymer for Granules

In order to prepare a choline alfoscerate-containing granules having the ingredients and contents as shown in Table 4, the effects of various kinds of polymers used to prepare granules were evaluated.

No Ingredient (mg) Example 3-1 3-2 3-3 3-4 3-5 3-6 a choline alfoscerate 400 400 400 400 400 400 b colloidal silicon dioxide 300 300 300 300 300 300 c polyvinylpyrrolidone 250 - - - - - hydroxypropylcellulose - 250 - - - - poloxamer - - 250 - - - polyox - - - 250 - - carrageenan - - - - 250 - hydroxypropylmethylcellulose (5 cp) - - - - - 250 d mannitol 125 125 125 125 125 125 e aspartame 15 15 15 15 15 15 f polyethyleneglycol6000 25 25 25 25 25 25 g sugar 850 850 850 850 850 850 h citric acid 20 20 20 20 20 20 i flavor 15 15 15 15 15 15 j water Quantity Quantity Quantity Quantity Quantity Quantity k ethanol Quantity Quantity Quantity Quantity Quantity Quantity Sum 2,000 2,000 2,000 2,000 2,000 2,000

The granules of Example 3 were prepared and evaluated by two methods similar to those of Example 2. That is, the granules were prepared and evaluated by a method using a fluidized bed granulator and a method using a general mixer.

In the case of Example 3-1, the viscosity of the granule liquid was low, the dissolution in the granular solvent (water) was fast, and the process condition was good in the spraying and mixing process. However, the possibility of moisture invasion was high, and there existed a concern about the implementation of choline alfoscerate which is a liquid main component. In the case of Example 3-2, the viscosity was relatively high during the preparation of the granulated liquid, the amount of the granular solvent was increased, and the process time was long, and the drying state and the time were relatively long. In the case of Example 3-3, the viscosity of the granule solution was low and the dissolution in the granule solvent (water) was fast, and the process state was good during the spraying and mixing process, but the coating efficiency was relatively low, and thus the main component was easily transferred or bleeded out. In the case of Example 3-4, the viscosity was low and the dissolution in the granular solvent (water) was quick when preparing granule liquid, and the process condition was good during the spraying and mixing process. However, there is a disadvantage that the polymer chain is broken over time due to poor stability of the polymer itself. In the case of Example 3-5, the viscosity was relatively high when the granule was prepared, and the drying state and the time were relatively long. As a result, Example 3-6 was the most preferable when considering the ease of manufacture, storage stability, and the like.

<Example 4> Dose ease evaluation

Ease of taking was evaluated using the existing capsules, soft capsules of the formulation of choline alfoscerate and Examples 2-4, which are granules according to the present invention. A single unit of the same amount was taken one by one, and the ease of taking was evaluated using the questionnaire. The results for the soft capsules are shown in Table 5, and the results of taking the granules according to the present invention are shown in Table 6 below. Group 1 is 20 to 29 years old, and Group 2 is 20 to 40 to 49 years old. , Group 3 is the result of evaluating 20 people aged 60 to 69 years.

Very Good (5) Good (4) Medium (3) Not good (2) Very bad (1) Total score Group 1 Number of people 3 4 8 4 One 64 score 15 16 24 8 One Group 2 Number of people One 2 5 7 3 45 score 5 8 15 14 3 Group 3 Number of people 0 2 4 9 5 43 score 0 8 12 18 5 Grand total 152

Very Good (5) Good (4) Medium (3) Not good (2) Very bad (1) Total score Group 1 Number of people 4 5 6 3 2 66 score 20 20 18 6 2 Group 2 Number of people 5 7 6 2 0 75 score 25 28 18 4 0 Group 3 Number of people 9 8 3 0 0 86 score 45 32 9 0 0 Grand total 227

As shown in Tables 5 and 6, the granule (powder) having a total score of 227 was about 50% higher than the soft capsule formulation having a total score of 152. Particularly, in the group of 20s, the ease of taking the two formulations Similarly, there was a nearly 50% difference in the older group, Group 3. Therefore, in the case of choline alfoscerate formulations, powders or granules prepared by solidifying the main ingredient may have a higher appeal than conventional formulations.

Example 5 Stability Evaluation

Properties and content under long-term preservation conditions (25 ℃, 60% RH) and accelerated conditions (40 ℃, 75% RH) using a conventional capsule choline alfoscerate formulation soft capsule and Example 2-4 granules according to the present invention The stability was evaluated through the change.

More specifically, the change in the properties of the existing soft capsule product and Examples 2-4 in HDPE bottles in large quantities, respectively, 4 weeks, 8 weeks, 12 weeks, 16 weeks to change the appearance over time under the long-term storage conditions and accelerated conditions , 20 weeks, 24 weeks were observed with the naked eye, the content change was measured by taking out some samples at the time of visual observation. The results of the soft capsule are shown in Table 7, and the results of Example 2-4 according to the present invention are shown in Table 8.

term Constellation content(%) Long-term preservation conditions Acceleration condition Long-term preservation conditions Acceleration condition contents film contents film Initial Good Good 101.3 - 101.3 - 4 Weeks Good Shape distortion. Sticking together. 100.4 - 94.4 3.9 8 Weeks Good Same as above 101.1 - 85.6 12.7 12 Weeks Good Same as above 100.0 - 66.7 28.1 16 Weeks Good Same as above 99.5 - 65.2 28.2 20 Weeks Good Same as above 99.0 0.8 64.1 27.8 24 Weeks Gelatin hardens hardly Same as above 98.6 1.1 65.0 28.6

term Statue content(%) Long-term preservation conditions Acceleration condition Long-term preservation conditions Acceleration condition Initial Good Good 101.3 101.3 4 Weeks Good Good 101.0 101.4 8 Weeks Good Good 100.9 101.4 12 Weeks Good Good 101.8 102.6 16 Weeks Good A little chunk of white sugar. 99.5 99.8 20 Weeks Good Same as above 101.4 100.4 24 Weeks Good Same as above 100.1 100.7

As shown in Tables 7 and 8, in the long-term storage conditions, in the case of Example 2-4 shows a good state until completion of 24 weeks, in the case of the existing soft capsule formulation, it was found that the gelatinous coating hardened after 24 weeks Could. In the accelerated condition, the powders (granules) of Example 2-4 showed good condition for up to 12 weeks, whereas in the conventional soft capsule formulation, the change in appearance was severe after 4 weeks.

In the case of content stability evaluation, Example 2-4 under the long-term preservation conditions is good until completion of 24 weeks, the soft capsule formulation began to transfer the main component to the film little by little after 20 weeks. In the accelerated condition, in Example 2-4, which is a powder, it shows a good state for up to 20 weeks, whereas in the conventional soft capsule formulation, the change in appearance is severe after 4 weeks, and as a result of film analysis, the transition progresses little by little and 12 weeks after acceleration. In 28% of the contents (main ingredient) transferred to the coating was found to be serious.

Claims (7)

Choline alfoscerate-containing pharmaceutical preparation, comprising choline alfoscerate adsorbed on colloidal silicon dioxide. The pharmaceutical formulation of claim 1, wherein the choline alfoscerate is adsorbed on 0.5 to 1.5 parts by weight of colloidal silicon dioxide based on the weight of choline alfoscerate. The pharmaceutical formulation of claim 2, wherein the choline alfoscerate-adsorbed silicon dioxide is prepared in granules using a water-soluble polymer. The pharmaceutical formulation of claim 3, wherein the water-soluble polymer is polyvinylpyrrolidone, hydroxypropylmethylcellulose, or a mixture thereof. The pharmaceutical formulation of claim 4, wherein the water-soluble polymer is hydroxypropylmethylcellulose. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is a powder or granules. (S1) adsorbing choline alfoscerate to 0.5 to 1.5 parts by weight of colloidal silicon dioxide relative to the weight of choline alfoscerate; And (S2) preparing colloidal silicon dioxide adsorbed choline alfoscerate into granules using hydroxypropylmethylcellulose, polyvinylpyrrolidone or a mixture thereof Method for producing a choline alfoscerate-containing pharmaceutical formulation comprising a.